Study of the radiologic and pathologic correlations for subsolid lung adenocarcinoma with the application of whole-mount sections (ECTOP1011)

Introduction

With the wide application of thoracic computed tomography, a high prevalence of pulmonary nodules, especially subsolid nodules, is increasingly detected (1-3). According to guidelines from the Fleischner Society in 2017, subsolid nodules are categorized into pure ground-glass opacity (GGO) nodules, and part-solid nodules having both GGO and solid components on thin-section computed tomography (TS-CT). Persistent subsolid nodules could be pathologically pre-invasive or invasive lung adenocarcinomas (4). Traditionally, GGO in a subsolid tumor on TS-CT tends to correspond to the lepidic pattern which is regarded as the pathologically non-invasive part, while the solid component has a greater chance of having the invasive part (5). According to the 8^th edition of the tumor-node-metastasis (TNM) staging of pulmonary adenocarcinoma, only the solid or invasive part is used as a descriptor of the T-categories for radiologically subsolid tumors or pathologically part-lepidic non-mucinous adenocarcinomas (6). This concept is supported by previous studies that using the invasive size could stratify the prognosis of patients better compared with using the total size of the tumors (7,8).

Clinically, GGO component could not only correspond to the lepidic pattern, but sometimes be pathologically non-lepidic patterns. Also, the solid component does not always correspond to the histologic invasiveness, sometimes a benign or a fibrous scar harboring a stromal invasive component (9). Accordingly, the pathologic features of pure GGO and part-solid tumors are still unclear, which need further investigation. Notably, pathologic analyses in previous studies were based on the conventional pathologic sections, which could not reflect the radiologic features of the whole lesion, because it was separated and its surrounding structures were disrupted (7,8,10). Up to date, there is no study using the whole-mount sections to address this issue.

Therefore, we performed this prospective study [Eastern Cooperative Thoracic Oncology Projects (ECTOP)1011] to analyze the radiologic and pathologic correlations of subsolid lung cancers with the application of the whole-mount sections. We aimed to clarify the radiologic and pathologic correlations, especially the histologic features of the GGO and solid components in subsolid tumors. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1063/rc).

Methods

Patients

This prospective cohort study (ECTOP1011) was registered in Clinicaltrials.gov (NCT05252676). Patients with radiologic subsolid lung adenocarcinoma who received segmentectomy or lobectomy at Fudan University Shanghai Cancer Center were enrolled. Patients with pathologic benign diseases or mucinous lung adenocarcinoma were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Review Board (IRB) of Fudan University Shanghai Cancer Center in China approved the study protocol and the publication of data (the IRB approval number: 2106237-23; the approval date: June 22, 2021). All enrolled patients provided informed written consent for the publication of the study data.

Radiologic evaluation

All patients received routine TS-CT and target scans. Examinations were performed using a Toshiba 320-row detector CT volume scanner (Aquilion ONE 320, TOSHIBA, Tokyo, Japan) with a Z-axis of 16 cm per volume scan. A small field-of-view CT target scan was performed on the target lesion. One radiologist (S.W.) and one thoracic surgeon (T.Y.) with more than 10 years of experience in chest radiology evaluated these CT images on lung window settings [window width, 1,600 Hounsfield units (HU); window level, −600 HU; width and interval, 1.0 and 1.0 mm]. The GGO nodule was defined as a radiologic lesion showing a hazy opacity without blocking underlying pulmonary vessels or bronchial structures on TS-CT (11). Definitions of the pure GGO and part-solid nodules were described in our previous studies (12,13). The maximum diameter on the single largest axial dimension measured on a lung window was recorded for the size of solid component and the whole nodule. When the solid component was irregular or multiple, multiple plane reconstruction was employed, and the largest was analyzed. When different opinions occurred, an agreement was reached through a discussion between the two evaluators.

Whole-mount section technique

The making process of the whole-mount sections included inflation, fixation, slicing, and embedding. After the targeted pulmonary lobe or segment was resected, the specimen was re-inflated by infusion of 10% buffered formalin using 12-gauge injection needles through the main or segmental bronchial stump. The specimen was inflated until the pleura over all segments was evenly swelled and became smooth. Then the inflated specimen was fixed into 10% buffered formalin for 24–48 hours. After fixation, the specimen was sectioned at intervals of 5 to 10 mm throughout the whole lobe or segment. Two to 6 representative slices of one specimen were selected and marked with colors to identify the three-dimensional position of the tumor for the subsequent radiologic and pathologic correspondence analysis. The colored sections were put into the special whole-mount boxes and were embedded in paraffin. Then, these embedded whole-mount sections were cut into 4-µm-thick slices, and stained with hematoxylin-eosin for pathological examination. The size of the whole-mount sections was 75 mm × 52 mm (Figure 1).

Figure 1 The making process of the whole-mount sections (the yellow circle was the tumor). (A) The resected lobe was re-inflated by infusion of 10% buffered formalin. (B) The specimen was sectioned after being fixed into 10% buffered formalin for 24–48 hours, and representative slices were selected. (C) The colored slice was put into the special whole-mount box and ready for paraffin embedding. (D) The finished whole mount section (hematoxylin-eosin staining; size: 75 mm × 52 mm).

Pathologic evaluation

All whole-mount slides were scanned and digitized using the Software NDP. view 2 (version 2.6, Hamamatsu Photonics K.K., Hamamatsu City, Japan) and K-Viewer (version 1.7, Konfoong Biotech, Ningbo, China). Two pathologists (X.S. and Y.L.) with more than 10 years of experience in thoracic malignancies evaluated all slides together. Pathologic diagnosis was made according to the 2021 World Health Organization (WHO) classification of tumors of the lung, pleura, thymus, and heart, and grading of the invasive lung adenocarcinoma was recorded (14). Histologic subtypes of adenocarcinoma including lepidic, acinar, papillary, micropapillary, and solid subtypes were identified, and the percentage of these subtypes in every slide was recorded. The lepidic pattern was regarded as a non-invasive part, while the non-lepidic pattern was regarded as an invasive part. The maximum diameters of the whole tumor and the invasive part were respectively recorded on every histologic slide. When the invasive regions were multiple, only the largest one was analyzed. When the invasive part contained fibrosis, the size of the fibrosis was included (5). The largest diameter of the whole tumor or invasive component on one of the slides was recorded as the maximum diameter of the tumor or the invasive part of the tumor. The presence of fibrosis, spread through alveolar space (STAS), lymphatic/nerve invasion, and pleural invasion were also recorded. When different opinions occurred, an agreement was reached through a discussion between the two pathologists. Pathologic staging was according to the 8^th edition of the TNM classification of lung cancer (6).

Radiologic and pathologic correspondence analysis

The radiologic and pathologic correspondence analysis included four steps: matching, overlapping, delineating, and analyzing. When the outlines of the tumor on the histologic section and on TS-CT were similar, the pathologic and radiologic sections were regarded as matched. When the anatomic locations among the vessels, bronchi, and tumor on the histologic section and on TS-CT could be one-to-one matched, the sections were regarded as well-matched. For well-matched sections, the radiologic solid component was delineated on the histologic section. The other region of the tumor on the histologic section was regarded as the GGO region. Histologic features were evaluated in the delineated solid and GGO region on the histologic sections, and the prevalence of histologic features was recorded. The additional details on the method for making the correspondence analysis were provided in Appendix 1 and Figure S1.

Statistical analysis

The primary endpoint was the radiologic and pathologic correlations of the tumor and the solid component. Especially, the prevalence of histologic features in the GGO and solid component regions on TS-CT was analyzed. The median maximum diameters between the radiologic and pathologic tumors and solid/invasive component were compared by using the non-parametric test. The Pearson or Spearman test was used for the correlation analysis. P values were two-sided with a significance level of 0.05. All statistical analyses were performed by using Microsoft Excel 2021 (Microsoft, Redmond, WA, USA) and SPSS version 19.0 (IBM, Chicago, IL, USA).

Results

Patients

From October 2020 to August 2022, a total of 103 patients with radiologic subsolid nodules who received segmentectomy or lobectomy were enrolled. One patient with pathologic mucinous lung adenocarcinoma was excluded. Finally, 102 patients including 69 females and 33 males were analyzed. There were 80 non-smokers and 22 smokers. The mean age was 58±9.6 (range, 36–78) years old. Fifty-six patients received lobectomy, and 46 patients received segmentectomy. One adenocarcinoma in situ, 32 minimal invasive adenocarcinomas, and 69 invasive adenocarcinomas were pathologically confirmed. For patients with invasive adenocarcinomas, there were 28 lepidic, 22 acinar, 18 papillary, and 1 micropapillary predominant invasive adenocarcinomas. According to the 2021 WHO grading system (14), there were 22 grade 1, 39 grade 2, and 8 grade 3 tumors. Moreover, there were 7 patients with STAS (7/69; 10.1%), 2 patients with lymphatic invasions (2/69; 2.9%), and 1 patient with pleural invasion. There were 19 tumors with fibrosis (19/102; 18.6%), in which 7 were minimal invasive adenocarcinomas, and 12 were invasive adenocarcinomas. Two patients with pathologically N2 diseases (2.0%) were confirmed (Figure S2), and the others had N0 diseases. Radiologically, there were 20 pure GGO and 82 part-solid nodules (Table 1).

Correlations between radiologic and pathologic tumor sizes and between solid and invasive component sizes in all patients

For the 102 patients, the median radiologic maximum tumor size was 22.2 (range, 11–61) mm, the median radiologic maximum solid component size was 6.8 (range, 0–31.7) mm, while the median pathologic maximum tumor size was 18 (range, 6.2–59.7) mm, the median pathologic maximum invasive component size was 9.6 (range, 0–51.4) mm. There was a significant correlation between the maximum radiologic and pathologic tumor sizes [correlation coefficient (r) =0.91, P<0.001]. Also, a significant correlation was noted between the maximum radiologic solid component size and pathologic invasive size (r=0.71, P<0.001). However, the median maximum radiologic tumor size was larger than the median maximum pathologic tumor size. The median difference was 4.2 mm (P<0.001). The median maximum radiologic solid component size was smaller than the median maximum pathologic invasive component size. The median difference was 2.8 mm (P=0.01) (Table 2, Figure S3).

Correlations between radiologic and pathologic tumor sizes and between solid and invasive component sizes in matched sections

A total of 320 whole-mount sections were obtained in 102 patients. Among them,135 radiologic and pathologic matched sections were identified in 85 patients. For these matched sections, the median radiologic maximum tumor size was 18.9 (range, 7.2–61.3) mm, the median radiologic maximum solid component size was 3.3 (range, 0–31.4) mm, while the median pathologic maximum tumor size was 16.6 (range, 6.5–59.7) mm, the median pathologic maximum invasive (non-lepidic) component size was 6.9 (range, 0–51.4) mm. Similarly, there was a significant correlation between the maximum radiologic and pathologic tumor sizes (r=0.87, P<0.001). Also, a significant correlation was noted between the maximum radiologic solid component size and pathologic invasive size (r=0.67, P<0.001). However, the median maximum radiologic tumor size was larger than the median maximum pathologic tumor size. The median difference was 2.3 mm (P=0.009). The median maximum radiologic solid component size was smaller than the median maximum pathologic invasive component size. The median difference was 3.6 mm (P<0.001) (Table 2, Figure S3).

Difference between clinical T and pathologic T categories in all patients

Clinically, there were 17 Tis, 21 T1mi, 33 T1a, 27 T1b, 3 T1c, and 1 T2a tumors. Pathologically, there were 1 Tis, 32 T1mi, 23 T1a, 37 T1b, 7 T1c, 1 T2b, and 1 T3 tumors. Accordingly, the clinical T staging in 49 patients (48%) was pathologically upgraded, the clinical T staging in 18 patients (17.7%) was pathologically downgraded, and the clinical T staging in 35 patients (34.3%) was pathologically equivalent.

Difference between clinical T and pathologic T categories in patients with matched sections

For 85 patients with the matched sections, clinically, there were 17 Tis, 13 T1mi, 27 T1a, 24 T1b, 3 T1c, and 1 T2a tumors. Pathologically, there were 27 T1mi, 18 T1a, 33 T1b, 5 T1c, 1 T2b, and 1 T3 tumors. Accordingly, the clinical T staging in 37 patients (43.5%) was pathologically upgraded, the clinical T staging in 14 patients (16.5%) was pathologically downgraded, and the clinical T staging in 34 patients (40%) was pathologically equivalent.

Histologic features of the pure GGO tumors

There were 100 well-matched radiologic and pathologic sections identified in 82 patients (Figure 2). For 19 radiologic pure GGO tumors, the prevalence of lepidic, acinar, and papillary subtypes was 100.0% (19/19), 84.2% (16/19), and 47.4% (9/19), respectively. No micropapillary or solid subtype was seen (Figures 2A,2B,3).

Figure 2 The prevalence of histologic subtypes in subsolid lung adenocarcinoma. (A) The pure GGO tumor and the pathologic GGO section. (B) The prevalence of histologic subtypes in pure GGO tumors. (C) The GGO section and the part-solid section of part-solid tumors. (D) The prevalence of histologic subtypes in the GGO sections and part-solid sections of part-solid tumors. GGO, ground-glass opacity.

Figure 3 Distribution of histologic subtypes in the pure GGO tumors. (A) One pure GGO tumor on thin section TS-CT. (B) The matched pathologic section by hematoxylin-eosin staining: blue region was tumor; green regions were the cystic airspaces; yellow region was ACN subtype; and black region was LEP subtype. (C,D) The LEP subtype (original magnification: ×50 and ×100). (E,F) The ACN subtype (original magnification: ×50 and ×100). ACN, acinar; GGO, ground-glass opacity; LEP, lepidic; TS-CT, thin-section computed tomography.

Histologic features of the GGO and solid components in the part-solid tumors

For 29 patients with part-solid tumors, 35 well-matched GGO sections were identified. The prevalence of lepidic, acinar, papillary, and micropapillary subtypes in the GGO sections was 100.0% (29/29), 62.1% (18/29), 44.8% (13/29), and 6.9% (2/29), respectively. No solid subtype was seen (Figures 2C,2D,4).

Figure 4 Distribution of histologic subtypes in the GGO sections of part-solid tumors. (A) The GGO section of one part-solid tumor on TS-CT. (B) The matched pathologic section by hematoxylin-eosin staining: black region was tumor; red regions were vessels; yellow region was MIP subtype; purple region was the ACN subtype; blue region was the PAP subtype; and green region was the LEP subtype. (C,D) The ACN subtype (original magnification: ×50 and ×100). (E,F) The MIP subtype (original magnification: ×50 and ×100). (G,H) The PAP subtype (original magnification: ×50 and ×100). (I,J) The LEP subtype (original magnification: ×50 and ×100). ACN, acinar; GGO, ground-glass opacity; LEP, lepidic; MIP, micropapillary; PAP, papillary; TS-CT, thin-section computed tomography.

For 42 patients with part-solid tumors, 45 well-matched part-solid sections were identified. In the GGO region on the part-solid sections, the prevalence of lepidic, acinar, papillary, and micropapillary subtypes was 100% (42/42), 83.3% (35/42), 57.1% (24/42), 11.9% (5/42), respectively. No solid subtype was seen.

In the solid component region on the part-solid sections, the prevalence of lepidic, acinar, papillary, micropapillary, and solid subtypes (Figure S4) was 19.0% (8/42), 95.2% (40/42), 59.5% (25/42), 26.2% (11/42), and 2.3% (1/42), respectively (Figure 2C,2D, Figure S5). Seven cases with STAS were seen in part-solid tumors (Table S1, Figure S6).

Discussion

The whole-mount section technique was first described in 1949 (15-17) and this technique has been well applied in studies on rectal cancer and prostate cancer in these years (18-20). For the routine pathologic examinations of lung cancers, when the lung specimen is resected, small pieces of tissue from the tumor are taken and cut into 4-µm-thick slices. The size of the pathologic sections is about 74 mm × 25 mm. The conventional sections may be suitable for the histologic confirmation, but could not continually and precisely reflect the radiologic features of the pulmonary lesion, because the lesion is separated and its surrounding structures are disrupted. Unlike the conventional histologic sections, the size of the whole-mount sections is 75 mm × 52 mm, and it contains the complete morphological features of the tumor and its surrounding structures. This advantage makes the precise matching of the same radiologic and pathologic sections possible, and facilitates the evaluation of histologic features for the GGO and solid components of the subsolid tumors.

There are a lot of radiologic and pathologic correlation studies using the conventional pathologic sections for radiologic subsolid lung cancers. Most of them focused on comparisons between radiologic and pathologic tumor and/or solid/invasive component sizes. For comparison of the tumor sizes, results in most studies were similar that the radiologic tumor size was larger than the pathologic tumor size (8,21,22). However, in comparison of the radiologic solid component size and pathologic invasive size, the results of these studies were inconsistent (7,8,21,22). In 2014, Lee and his colleagues evaluated the correlation between the radiologic and pathologic sizes of the solid and invasive components in 59 subsolid lung adenocarcinomas. Their results indicated that the solid component size was similar to the pathologic invasive size in two-dimensional measurement, whereas the solid component size was larger than the pathologic invasive size in three-dimensional measurement (8). In 2017, Aokage and his colleagues analyzed 1,792 lung cancers, of which 26% were radiologic subsolid tumors, to evaluate the correlation between the solid component size on TS-CT and pathologic invasive size in the new T classification. Their results indicated that the radiologic solid size and pathologic invasive size showed a strong linear correlation, but the radiologic solid component size was slightly overestimated compared with the pathologic invasive size (7). Contrarily, in 2021, Ahn and his colleagues compared the radiologic solid component size with the pathologic invasive size by using the deep learning algorithm in 448 subsolid lung cancers. Their results indicated that measurements by the deep learning algorithm and radiologists both underestimated the pathologic invasive component size (21). The most possible explanation for the inconsistent results was that most pathologic measurements were based on the conventional histologic sections, and the radiologic and pathologic sections might not be the same sections when comparing the solid/invasive component sizes. Therefore, we applied the whole-mount section technique to precisely match the radiologic and pathologic sections, so as to ensure the size comparisons between the same sections. Results in this prospective study indicated that the radiologic solid component size was smaller than the pathologic invasive size, whereas the radiologic tumor size was larger than the pathologic invasive size.

The question was why the radiologic solid component size was smaller than the pathologic invasive size. Our hypothesis was that there might be a pathologically invasive part in the GGO region for the subsolid tumors (9). Therefore, we further analyzed the histologic features of the GGO and solid components on TS-CT in 82 patients with the well-matched sections, and results indicated that there existed pathologically invasive component in pure GGO tumors, and there was micropapillary subtype, but no solid subtype in the GGO region of part-solid tumors. The distributions of these histologic subtypes in the GGO components verified our hypothesis and explained why the pathologic invasive component size was radiologically underestimated.

According to the 8^th TNM classification of lung cancer, only the size of solid part or the invasive size on pathology is used as a descriptor of clinical or pathologic T-categories, because the radiologic GGO versus solid part traditionally tends to correspond respectively to lepidic versus invasive patterns seen pathologically (5,6). However, our results showed that this correlation was not that absolute. There were pathologic invasive patterns in GGO regions, thus the size of invasive components was underestimated. Additionally, there were fibrosis and inflammation in the solid component region, besides the invasive subtypes. The presence of fibrosis and inflammation might overestimate the size of solid component (Figure S7). Especially, in this study, the clinical T stages in nearly 50% of patients were pathologically upgraded. This finding suggested that the current clinical T staging of the subsolid lung cancers might be underestimated.

Moreover, clarifying the histologic features in the GGO and solid components is important for us when making the appropriate surgical strategy for patients with the subsolid tumors. According to our results, there was no high-grade subtype or STAS in the pure GGO tumors. This could explain the favorable prognosis of the pure GGO tumors, and the sub-lobar resection should be selected (23). Nevertheless, there were nearly 28.5% micropapillary/solid subtypes in the solid component, and 17.1% micropapillary subtypes in the GGO component in part-solid tumors. In addition, there were seven cases with STAS in part-solid tumors. Detection of high-grade subtypes in both the GGO and solid components could explain the inferior prognosis (13,24), and the sub-lobar resection should be cautiously adopted combined with the results from previous studies (25-27).

Several limitations should be noted. Firstly, it was unclear whether direct measurement of the diameter of the pathologic invasive component was better than estimation by the invasive area, especially for the tumors with multifocal invasive components. According to the recommendation of the International Association for the Study of Lung Cancer (IASLC) lung cancer staging committee (5), we chose to directly measure the maximum diameter of the largest invasive part for those with multiple ones. Secondly, the boundary between the histologic invasive and non-invasive part in some cases was hard to distinguish. Accordingly, we re-inflated the resected specimens and they were subsequently fixed in an inflated state. This procedure could eliminate the disturbance due to the alveolar collapse. Moreover, two experienced pathologists evaluated all these sections together, and discussed with each other to reach a consensus when different opinions occurred. Thirdly, the interobserver agreement for differentiating between the GGO and solid components was not analyzed, because the two evaluators performed the radiologic evaluations together. According to our previous study (13), the inter-observer and intra-observer agreement values for differentiating between the subsolid and pure solid lung nodules were satisfactory. Lastly, subjective errors may have occurred during the matching of radiologic and pathologic sections. In the near future, incorporating artificial intelligence tools such as some machine learning algorithms and deep-learning techniques could enhance the efficiency and accuracy of the matching process, further reducing potential errors.

Conclusions

In conclusion, this is the first study using the whole-mount sections to clarify the radiologic and pathologic correlations for subsolid lung cancers. Results indicated that pathologic invasive component size was radiologically underestimated, and the clinical T staging was pathologically upgraded. For pure GGO tumors, there were invasive components, mainly acinar and papillary subtypes, but no high-graded subtypes. For the part-solid tumors, besides acinar and papillary subtypes, there were high-graded subtypes in both of the GGO and solid components. No STAS was seen in pure GGO tumors, while the prevalence of STAS was 10.1% in part-solid tumors.

Acknowledgments

The abstract of this study was accepted as a poster presentation in the 2023 World Conference on Lung Cancer, which was held on September 9–12, 2023 in Singapore.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1063/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1063/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1063/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 81930073), the Shanghai Science and Technology Innovation Action Project (No. 20JC1417200), the Cooperation Project of Conquering Major Diseases in Xuhui District (No. XHLHGG202101), the National Key R&D Program of China (No. 2022YFA1103900), and the Shanghai Science and Technology Commission General Project (No. 21ZR1415100).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1063/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board (IRB) of Fudan University Shanghai Cancer Center in China (the IRB approval number: 2106237-23; the approval date: June 22, 2021) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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